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1.
Sook Ryun Park Yong Sang Hong Hyeong-Seok Lim Moon-Woo Seong Sun-Young Kong Sun Young Kim Young-Iee Park Kyung Hae Jung 《Cancer chemotherapy and pharmacology》2013,72(5):953-964
Purpose
We conducted a phase I study of S-1 combined with irinotecan and oxaliplatin (TIROX) to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety, pharmacokinetics, pharmacogenetics, and preliminary efficacy in patients with metastatic colorectal cancer (MCRC) or metastatic gastric cancer (MGC).Methods
Patients received escalating doses of S-1 (30–40 mg/m2 b.i.d.) orally on days 1–14, an escalating dose of intravenous irinotecan (120–150 mg/m2) on day 1, and a fixed dose of intravenous oxaliplatin (85 mg/m2) on day 1 every 3 weeks.Results
Twenty-three patients (10 MCRC, 13 MGC; 13 chemonaive, 10 previously treated for metastatic disease) were treated across six dose levels. Because only one patient experienced a dose-limiting toxicity of grade 3 anorexia at the highest dose level (S-1 40 mg/m2 b.i.d., irinotecan 150 mg/m2, and oxaliplatin 85 mg/m2) (n = 8), the MTD was not obtained, and this level was established as the RD. With a median of 10 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (43 %), diarrhea (13 %), and nausea (13 %). In 22 efficacy-evaluable patients, the objective tumor response rate was 59.1 % (75 % for both MCRC and MGC in the first-line setting) and the disease control rate was 100 %. The exploratory pharmacokinetic/pharmacogenetic study showed that CYP2A6 variants (*4, *7, *9) are associated with a lower metabolic ratio of S-1 (exposure ratio of 5-fluorouracil to tegafur).Conclusions
The new triplet TIROX regimen has shown promising antitumor activity and a favorable toxicity profile in patients with MCRC and MGC. 相似文献2.
S. Fushida J. Kinoshita M. Kaji Y. Hirono F. Goda Y. Yagi K. Oyama Y. Sudo Y. Watanabe T. Fujimura 《Cancer chemotherapy and pharmacology》2013,71(5):1265-1272
Purpose
We designed a phase I/II trial of intraperitoneal (IP) docetaxel plus S-1 to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate its efficacy and safety in gastric cancer patients with peritoneal carcinomatosis (PC).Methods
Patients with PC confirmed by laparoscopy or laparotomy received IP docetaxel on days 1 and 15 and S-1 (80 mg/m2) on days 1–14 every 4 weeks.Results
In the phase I part (n = 12), each cohort received escalating doses of docetaxel (35–50 mg/m2); the MTD was determined to be 50 mg/m2 and the RD was determined to be 45 mg/m2. Dose-limiting toxicities included grade 3 febrile neutropenia and grade 3 diarrhea. In the phase II part (n = 27), the median number of courses was 4 (range 2–11). The 1-year overall survival (OS) rate was 70 % (95 % confidence interval 53–87 %). The overall response rate was 22 % and peritoneal cytology turned negative in 18 of 22 (81 %) patients. The most frequent grade 3/4 toxicities included anorexia (19 %), neutropenia (7 %), and leukopenia (7 %).Conclusion
IP docetaxel plus S-1 is active and safety in gastric cancer patients with PC. 相似文献3.
Hitoshi Kusaba Taito Esaki Junji Kishimoto Keita Uchino Shuji Arita Hozumi Kumagai Kenji Mitsugi Koichi Akashi Eishi Baba 《Cancer chemotherapy and pharmacology》2013,71(1):29-34
Purpose
The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan has been reported to be a promising regimen for advanced colorectal cancer. However, the safety and efficacy of bevacizumab (BV) to combine with irinotecan and S-1 has not been determined. The aim of the study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BV combined with irinotecan plus S-1, and to observe the safety and efficacy of this regimen as second-line chemotherapy in patients with advanced colorectal cancer.Methods
This study initially had been planned as a phase I/II study. Eighty mg/m2 of irinotecan on days 1 and 8, 80 mg/m2 of S-1 for 14 consecutive days, and two doses of BV (Level 1; 10 mg/kg, Level ?1; 7.5 mg/kg) were administered on day 1 every 3 weeks.Results
Fourteen patients were enrolled in phase I of the study between January 2008 and September 2010. Dose-limiting toxicities were diarrhea, abdominal pain, and infection. The MTD and RD of BV were determined to be 10 mg/kg and 7.5 mg/kg, respectively. The main adverse events were leukopenia, anorexia, and diarrhea. There were no treatment-related deaths. An independent review committee was scheduled to evaluate safety in phase I, but this trial closed early due to toxicity.Conclusions
This study identified the risk of gastrointestinal toxicity with the combination of irinotecan, S-1 and BV as second-line chemotherapy in patients with advanced colorectal cancer. 相似文献4.
Norisuke Nakayama Kenji Ishido Keisho Chin Ken Nishimura Mizutomo Azuma Satoshi Matsusaka Yasuhiro Inokuchi Satoshi Tanabe Yosuke Kumekawa Wasaburo Koizumi 《Gastric cancer》2017,20(2):350-357
Background
In Japan, S-1, an oral fluoropyrimidine, plus cisplatin is a standard regimen for advanced gastric cancer, whereas nab-paclitaxel is a treatment option. We aimed to evaluate the tolerance, pharmacokinetics, safety, and clinical efficacy of S-1 combined with nab-paclitaxel in patients with advanced gastric cancer in a phase 1 study.Methods
The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus nab-paclitaxel. The study was designed in accordance with a standard 3 + 3 method. Patients received 3-week cycles of treatment. S-1 was administered orally at 80 mg/m2 twice daily for 14 days, and nab-paclitaxel was administered as an intravenous infusion at 180, 220, or 260 mg/m2 on day 1 or 8.Results
Among the 16 patients enrolled, dose-limiting toxicity was observed in one patient at level 2a (S-1 80 mg/m2 twice daily plus nab-paclitaxel 220 mg/m2 on day 1). The MTD was not obtained, but the RD was established as level 3a (S-1 80 mg/m2 twice daily plus nab-paclitaxel 260 mg/m2 on day 1). The most common grade 3–4 toxicity was neutropenia (62.5 %). The overall response rate was 54.5 %. The pharmacokinetic profiles of coadministered S-1 and paclitaxel were comparable to those of nab-paclitaxel or S-1 alone.Conclusions
Based on the present results, the RD was determined as level 3a (S-1 80 mg/m2 twice daily plus nab-paclitaxel 260 mg/m2 on day 1). This combination therapy was well tolerated and showed antitumor efficacy in patients with advanced gastric cancer.5.
Yoda S Soejima K Yasuda H Naoki K Kawada I Watanabe H Nakachi I Satomi R Nakayama S Ikemura S Terai H Sato T Morosawa M Asano K 《Cancer chemotherapy and pharmacology》2011,67(3):717-722
Background
This phase I study was conducted to evaluate the feasibility and to determine the recommended doses of the combination therapy of S-1 and irinotecan (CPT-11) in patients with advanced non-small cell lung cancer (NSCLC) as second-line treatment.Methods
Patients with NSCLC who were previously treated with one chemotherapy regimen and had a performance status of 0 or 1 were eligible. CPT-11 was administered at 60 mg/m2 (level 1), 80 mg/m2 (level 2) on days 1 and 8, and oral S-1 was administered at 80 mg/day for body surface area (BSA) less than 1.25 m2, 100 mg/day for BSA 1.25–1.5 m2, and 120 mg/day for BSA more than 1.5 m2 on days 1–14 every 3 weeks. The dose-limiting toxicity (DLT) was defined as grade 4 leukocytopenia or neutropenia, grade ≥3 neutropenia with fever over 38°C, grade ≥3 thrombocytopenia, or grade ≥3 major nonhematological toxicities.Results
Nine patients were enrolled in the study. None of 3 patients enrolled in level 1 had any DLT. Of 6 patients in level 2, 2 patients had grade 3 diarrhea and one had grade 3 interstitial pneumonia. Level 1 was declared as the recommended dose.Conclusion
The feasibility of the combination therapy of S-1 and CPT-11 was shown in the second-line setting for the treatment of advanced NSCLC. The recommended dose of CPT-11 was 60 mg/m2 combined with standard dose of S-1 for phase II trials of pretreated advanced NSCLC patients. 相似文献6.
Markus Moehler Rolf Mahlberg Volker Heinemann Radka Obermannová Eugen Kubala Bohuslav Melichar Arndt Weinmann Paul Scigalla Marietta Tesařová Petr Janda Fabienne Hédouin-Biville Wasat Mansoor 《Gastric cancer》2017,20(2):358-367
Background
This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS).Methods
Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m2 followed by oxaliplatin 130 mg/m2 (maximum 8 cycles) and then S-1 [20 mg/m2 (cohort 1) or 25 mg/m2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2–14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer.Results
DLT was reported for two of the five patients in cohort 2, defining 20 mg/m2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m2 twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations.Conclusions
The promising activity of EOS (S-1 dose level, 25 mg/m2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.7.
Xiaohui Ge Wenyan Zhao Xiaocang Ren Yongqiang Wang Zhigang Li Yanqi Li Yue’e Liu Qiang Lin 《中德临床肿瘤学杂志》2012,11(8):449-451
Objective
The aim of this study was to define the maximum-tolerated dose (MTD) and observe the toxicity of escalating topotecan combined whole brain radiotherapy for brain metastasis in lung cancer.Methods
Patients with brain metastasis of lung cancer received conventional fractionation radiotherapy, with 5 daily fractions of 2 Gy per week, the total radiation dose was 40 Gy, while the larger lesions were boosted to 50–60 Gy. The initial dose of topotecan was 1.0 mg/m2. Escalation dose was 0.25 mg/m2. Every cohort contained at least 3 patients. If no dose-limiting toxicity (DLT) was observed, the next dose level was opened for entry. These courses were repeated until DLT appeared. MTD was declared as one dose level below which DLT appeared.Results
Eighteen patients were recruited. Two cases of grade 3 leucopenia/neutropenia was observed as DLT at the level of topotecan 2.0 mg/m2. MTD of topotecan was defined as 1.75 mg/m2. The major side effects were leucopenia/neutropenia, nausea and vomiting.Conclusion
Topotecan combined with whole brain radiotherapy for brain metastasis in lung cancer is well tolerated. Maximum-tolerated dose of topotecan is 1.75 mg/m2, once a week of a total of four. 相似文献8.
Sun Jin Sym Min-Hee Ryu Hye Jin Kang Sung Sook Lee Heung-Moon Chang Jae Lyun Lee Tae Won Kim Jeong Hwan Yook Sung Tae Oh Byung Sik Kim Yoon-Koo Kang 《Cancer chemotherapy and pharmacology》2010,66(2):373-380
Purpose
Adding docetaxel to cisplatin and 5-fluorouracil (5-FU) (DCF) significantly improved clinical efficacy in advanced gastric cancer (AGC). To further improve the efficacy and tolerability, we substituted oxaliplatin for cisplatin and capecitabine for 5-FU in the DCF regimen and performed a phase I study to determine the recommended dose (RD) and dose-limiting toxicity (DLT) of docetaxel, capecitabine and oxaliplatin (DXO) combination in patients with AGC.Materials and methods
Previously untreated patients with histologically proven metastatic AGC and ECOG performance status 0–2 were enrolled. Docetaxel and oxaliplatin were administered i.v. on day 1. Capecitabine was administered orally bid on days 1–14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first two cycles of treatment.Results
Twenty-one patients were enrolled: 15 patients in dose-escalation phase and 6 patients in the extension at the RD. Median age was 50 years (range 21–65 years). At dose level 3 (60 mg/m2 docetaxel, 1,000 mg/m2 capecitabine, 100 mg/m2 oxaliplatin), 1 diarrhea (DLT) was found among 6 patients while at dose level 4 (60 mg/m2 docetaxel, 800 mg/m2 capecitabine, 130 mg/m2 oxaliplatin), 2 DLTs (febrile neutropenia and diarrhea) were observed among 3 patients. Therefore, the dose level 3 was determined as RD. DLTs include grade 3 diarrhea and febrile neutropenia. Cumulative (all cycles) grade 3/4 toxicity included neutropenia (75%), leucopenia (50%), febrile neutropenia (25%), diarrhea (17%), and neuropathy (17%). Of 14 patients with measurable lesions, 11 achieved partial response and 3 showed stable disease.Conclusion
The RD of the DXO regimen in patients with AGC is capecitabine 1,000 mg/m2 twice daily on days 1–14, in combination with decetaxel 60 mg/m2 (day 1) and oxaliplatin 100 mg/m2 (day 1) repeated every 3 weeks. The DXO regimen seems to have promising activity and offers an easy alternative to DCF. The toxicities appear to be still substantial, but manageable. 相似文献9.
Yo-ichi Yamashita Akinobu Taketomi Shinji Itoh Norifumi Harimoto Kazutoyo Morita Takasuke Fukuhara Shigeru Ueda Kensaku Sanefuji Keishi Sugimachi Tsuyoshi Tajima Yoshihiko Maehara 《Cancer chemotherapy and pharmacology》2010,65(2):301-307
Purpose
Lipiodol Ultra-Fluid (Lipiodol®), an oily contrast medium, is selectively retained in hepatocellular carcinoma (HCC) through hepatic arterial infusion. DDP-H (IA-call®) developed as a CDDP powder, and may be a possible chemotherapeutic agent with lipiodol. We carried out a phase I/II study of the lipiodolization using DPP-H in patients with unresectable HCC.Methods
Phase I and pharmacokinetic study: The dose-limiting toxicity (DLT), the maximum tolerance dose (MTD), and the recommended dose (RD) were determined using a modified Fibonacci scheme. The concentration–time profile of total platinum in plasma was analyzed. Phase II study: Thirty-five patients with unresectable HCC received lipiodolization using DDP-H under RD, and the efficacy and safety were assessed.Results
DLT was grade 3 vomiting at 40 mg/m2. Therefore, MTD and RD were 35 mg/m2. The peak of total platinum in plasma was over 1.0 μg/ml at 40 mg/m2 at 30 min after infusion. Of the 35 patients, 16 (45.7%) demonstrated complete responses, and 4 (11.4%) demonstrated partial responses with an additional 9 patients (25.7%) having stable diseases, as assessed by RECIST. Grade 3 thrombocytopenia was found in 1 patient (2.9%), grade 2 hyperbilirubinemia was found in 2 patients (5.7%), and grade 2 vomiting was found in 4 patients (11.4%).Conclusion
Lipiodolization using DDP-H at 35 mg/m2 is effective and well tolerated in patients with unresectable HCC. 相似文献10.
Inkeun Park Jae-Lyun Lee Min-Hee Ryu Heung Moon Chang Tae-Won Kim Sun-Jin Sym Sung Sook Lee Geundoo Jang Changhoon Yoo Kyun-Seop Bae Yoon-Koo Kang 《Cancer chemotherapy and pharmacology》2010,65(3):473-480
Background
We aimed to determine the maximum-tolerated dose (MTD) of S-1 when given with oxaliplatin, to evaluate S-1 pharmacokinetics, and to determine the efficacy and safety of this regimen as a first-line treatment for advanced gastric cancer (AGC).Methods
Oxaliplatin was fixed at a dose of 130 mg/m2 on day 1 (D1). S-1 was administered from D1 to D14 of a 3-week cycle, and escalated by 10 mg/m2 per day from 70 mg/m2 per day up to 100 mg/m2 per day. Pharmacokinetic analyses were performed following a single dose of S-1 on D-5 and D1 of the first cycle.Results
In phase I (n = 18), MTD was not defined. In phase II (n = 47) with the planned maximum dose, partial response was achieved in 26 patients (55.3%) and stable disease in 14 patients (29.8%). The median time to progression was 6.6 months (95% CI 4.0–9.2 months) and the median overall survival was 12.5 months (95% CI 9.2–15.9 months). Frequent grade 3/4 toxicities included thrombocytopenia (39%), neutropenia (28%), anemia (17%), and leukopenia (13%). There was one grade 5 febrile neutropenia during the first cycle.Conclusions
The pharmacokinetics of S-1 was not influenced by oxaliplatin. S-1/Oxaliplatin combination therapy is highly active against AGC and has a favorable toxicity profile. 相似文献11.
Brian S. Choi Dona B. Alberti William R. Schelman Jill M. Kolesar James P. Thomas Rebecca Marnocha Jens C. Eickhoff S. Percy Ivy George Wilding Kyle D. Holen 《Cancer chemotherapy and pharmacology》2010,66(5):973-980
Purpose
3-AP is a ribonucleotide reductase inhibitor and has been postulated to act synergistically with other chemotherapeutic agents. This study was conducted to determine the toxicity and antitumor activity of 3-AP with irinotecan. Correlative studies included pharmacokinetics and the effects of ABCB1 and UGT1A1 polymorphisms.Methods
The treatment plan consisted of irinotecan on day 1 with 3-AP on days 1–3 of a 21-day cycle. Starting dose was irinotecan 150 mg/m2 and 3-AP 85 mg/m2 per day. Polymorphisms of ABCB1 were evaluated by pyrosequencing. Drug concentrations were determined by HPLC.Results
Twenty-three patients were enrolled, 10 men and 13 women. Tumor types included seven patients with pancreatic cancer, four with lung cancer, two with cholangiocarcinoma, two with mesothelioma, two with ovarian cancer, and six with other malignancies. Two patients experienced dose-limiting toxicity (DLT) at dose level 1, requiring amendment of the dose-escalation scheme. Maximal tolerated dose (MTD) was determined to be 3-AP 60 mg/m2 per day and irinotecan 200 mg/m2. DLTs consisted of hypoxia, leukopenia, fatigue, infection, thrombocytopenia, dehydration, and ALT elevation. One partial response in a patient with refractory non-small cell lung cancer was seen. Genotyping suggests that patients with wild-type ABCB1 have a higher rate of grade 3 or 4 toxicity than those with ABCB1 mutations.Conclusions
The MTD for this combination was 3-AP 60 mg/m2 per day on days 1–3 and irinotecan 200 mg/m2 on day 1 every 21 days. Antitumor activity in a patient with refractory non-small cell lung cancer was noted at level 1. 相似文献12.
Shogo Kobayashi Hiroaki Nagano Daisuke Sakai Hidetoshi Eguchi Etsuro Hatano Masashi Kanai Satoru Seo Kojiro Taura Yutaka Fujiwara Tetsuo Ajiki Shigekazu Takemura Shoji Kubo Hiroaki Yanagimoto Hideyoshi Toyokawa Akihito Tsuji Hiroaki Terajima Satoshi Morita Tatsuya Ioka 《Cancer chemotherapy and pharmacology》2014,74(4):699-709
Background
Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy.Methods
Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800–1,000 mg/m2 gemcitabine on days 1, 8, and 15 and then every 3–4 weeks or 40–80 mg/m2/day S-1 on days 1–28 and every 3–6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm.Results
Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10 % of DLT, the recommended dose was 1,000 mg/m2 gemcitabine biweekly and 80 mg/m2/day S-1 on days 1–28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted.Conclusion
We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10 %. 相似文献13.
Shivaani Kummar Martin E. Gutierrez Erin R. Gardner William D. Figg Giovanni Melillo Janet Dancey Edward A. Sausville Barbara A. Conley Anthony J. Murgo James H. Doroshow 《Cancer chemotherapy and pharmacology》2010,65(2):383-389
Purpose
UCN-01 potently inhibits protein kinase C, phosphatidylinositide-dependent kinase-1, and checkpoint kinase 1, which are involved in regulating cell cycle progression. We designed a phase I study to determine the maximum tolerated dose (MTD) of UCN-01 with prednisone in patients with advanced malignancies.Methods
UCN-01 was administered as a continuous intravenous infusion over 72 h in cycle 1 and 36 h in subsequent cycles. Prednisone was given orally at 60 mg/m2 per day for five consecutive days within each 28-day cycle. Standard dose escalation was employed, and MTD was defined as the dose at which no more than one of six patients experienced a dose-limiting toxicity (DLT). Plasma pharmacokinetics of UCN-01 were assessed.Results
Fifteen patients received a total of 55 courses of treatment. The MTD and the recommended phase II dose of UCN-01 in this combination is 72 mg/m2 total dose over 72 h for cycle 1 followed by 36 mg/m2 per cycle over 36 h. All patients experienced hyperglycemia but responded to insulin treatment. Hypophosphatemia was a DLT in two patients. There were no cumulative toxicities. No objective responses were observed, but five patients had stable disease, including two patients with lymphoid malignancies who had prolonged disease stabilizations. UCN-01 has a long terminal half-life and low clearance; there was wide inter-patient variability in peak concentrations.Conclusion
UCN-01 can be safely administered in combination with prednisone without unacceptable toxicity. The prolonged stable disease in two patients with lymphoid malignancies is a proof of principle for the evaluation of cyclin-dependent kinase inhibitors in oncology. 相似文献14.
Tadahiro Shoji Eriko Takatori Yoshitaka Kaido Hideo Omi Yoshihito Yokoyama Hideki Mizunuma Michiko Kaiho Takeo Otsuki Tadao Takano Nobuo Yaegashi Hiroshi Nishiyama Keiya Fujimori Toru Sugiyama 《Cancer chemotherapy and pharmacology》2014,73(5):895-901
Purpose
A phase I clinical study was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan hydrochloride (CPT-11) in CPT-11/pegylated liposomal doxorubicin (PLD) combination therapy, a novel treatment regimen for platinum- and taxane-resistant recurrent ovarian cancer.Methods
Pegylated liposomal doxorubicin was administered intravenously on day 3 at a fixed dose of 30 mg/m2. CPT-11 was administered intravenously on days 1 and 15, at a dose of 50 mg/m2 on both days. One course of chemotherapy was 28 days, and patients were given a maximum of six courses, with the CPT-11 dose being increased in increments of 10 mg/m2 (level 1, 50 mg/m2; level 2, 60 mg/m2; level 3, 70 mg/m2; level 4, 80 mg/m2) to determine MTD and RD.Results
During the period from April 2010 to March 2013, three patients were enrolled for each level. In the first course, no dose-limiting toxicity occurred in any of the patients. Grade 4 neutropenia was observed in two of three patients at level 4. At level 4, the antitumor effect was a partial response (PR) in two of the three patients and stable disease (SD) in one. At level 3, one of the three patients showed PR and two had SD. At level 4, the start of the next course was postponed in two of three patients. In addition, one patient at level 4 experienced hemotoxicity that met the criteria for dose reduction in the next course. The above results suggested that administration of CPT-11 at dose level 5 (90 mg/m2) would result in more patients with severe neutropenia and in more patients requiring postponement of the next course or a dose reduction. Based on the above, the RD of CPT-11 was determined to be 80 mg/m2.Conclusions
The results suggest that CPT-11/PLD combination therapy for recurrent ovarian cancer is a useful treatment method with a high response rate and manageable adverse reactions. In the future phase II study, the safety and efficacy of this therapy will be assessed at 80 mg/m2 of CPT-11 and 30 mg/m2 of PLD. 相似文献15.
Michael B. Jameson Danny Rischin Mark Pegram John Gutheil Adam V. Patterson William A. Denny William R. Wilson 《Cancer chemotherapy and pharmacology》2010,65(4):791-801
Purpose
PR-104 is a “pre-prodrug” designed to be activated to a dinitrobenzamide nitrogen mustard cytotoxin by nitroreduction in hypoxic regions of tumors. This study was conducted to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetics (PK) of PR-104 in patients with advanced solid tumors.Methods
Patients with solid tumors refractory or not amenable to conventional treatment were evaluated in a dose-escalation trial of PR-104 administered as a 1-h intravenous (IV) infusion every 3 weeks. The plasma PK of PR-104 and its primary metabolite, PR-104A, were evaluated.Results
Twenty-seven patients received a median of two cycles of PR-104 in doses ranging from 135 to 1,400 mg/m2. The MTD of PR-104 as a single-dose infusion every 3 weeks was established as 1,100 mg/m2. One of six patients treated at 1,100 mg/m2 experienced DLT of grade 3 fatigue. Above the MTD, the DLTs at 1,400 mg/m2 were febrile neutropenia and infection with normal absolute neutrophil count. No objective responses were observed, although reductions in tumor size were observed in patients treated at doses ≥550 mg/m2. The plasma PK of PR-104 demonstrated rapid conversion to PR-104A, with approximately dose-linear PK of both species.Conclusions
PR-104 was well tolerated at a dose of 1,100 mg/m2 administered as an IV infusion every 3 weeks. The area under the PR-104A plasma concentration–time curve at this dose exceeded that required for activity in human tumor cell cultures and xenograft models. The recommended dose of PR-104 as a single agent for phase II trials is 1,100 mg/m2 and further trials are underway. 相似文献16.
Hara T Omura K Hirano M Asada Y Munemoto Y Sakamoto J 《Cancer chemotherapy and pharmacology》2007,59(5):631-636
Purpose
A phase I study of TCF therapy, which consists of paclitaxel (TXL: Taxol®) + cisplatin (CDDP) + 5-fluorouracil (5-FU), in advanced gastric cancer patients was performed to determine the recommended dose (RD) for a phase II study by checking the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of 5-FU above the fixed dose of TXL and CDDP.Methods
The doses of TXL and CDDP were fixed at 80 and 25 mg/m2, respectively, while that of 5-FU was increased by 100 mg/m2 in each cohort from 300 mg/m2 (level 1) to a maximum of 600 mg/m2 (level 4). One cycle consisted of administration of these agents once per week for 3 weeks, every 4 weeks.Results
A total of twelve eligible patients were included in this study. At level 1, two of three cases showed grade 3 leukopenia. At level 2, one of three cases showed grade 4 neutropenia (recovered within 3 days), and another one case showed grade 3 neutropenia. At level 3, one of three cases showed grade 3 neutropenia, and at level 4, one of three cases showed grade 4 neutropenia (recovered within 3 days), with grade 3 neutropenia in the other two cases. Even at the highest dose administered, none of the patients showed DLT. Moreover, no non-hematological toxicity judged to be DLT was observed through all levels. Six of the twelve patients had measurable disease, and the overall response rate was 83%.Conclusions
Although the MTD level was not determined, based on the observed efficacy and the results of other clinical trials, the recommended doses of TXL, CDDP, and 5-FU for the TCF regimen were set as 80, 25, and 600 mg/m2, respectively, and a phase II study to investigate the clinical effectiveness and safety of this regimen has now begun. 相似文献17.
Paul K. Paik Charles M. Rudin Andrew Brown Naiyer A. Rizvi Naoko Takebe William Travis Leonard James Michelle S. Ginsberg Rosalyn Juergens Susan Markus Leslie Tyson Sara Subzwari Mark G. Kris Lee M. Krug 《Cancer chemotherapy and pharmacology》2010,66(6):1079-1085
Purpose
To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies.Patients and methods
Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m2 by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m2 was given concurrently as an IV infusion on days 1–5 of each cycle.Results
Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m2 on day 1, 14 mg/m2 on days 1 and 3, and 20 mg/m2 on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m2; no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m2 on day 1, the level was escalated to 14 mg/m2 on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m2 on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks.Conclusion
Obatoclax mesylate administered at 14 mg/m2 IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m2 IV on days 1–5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients. 相似文献18.
Yousuke Nakai Hiroyuki Isayama Kei Saito Takashi Sasaki Naminatsu Takahara Tsuyoshi Hamada Suguru Mizuno Koji Miyabayashi Keisuke Yamamoto Dai Mohri Hirofumi Kogure Natsuyo Yamamoto Kenji Hirano Hideaki Ijichi Keisuke Tateishi Minoru Tada Kazuhiko Koike 《Cancer chemotherapy and pharmacology》2014,74(5):911-915
Purpose
In our previous randomized controlled trial, the addition of S-1 to gemcitabine for advanced pancreatic cancer did not prolong overall survival (OS) significantly, despite its higher response rate and longer progression-free survival (PFS). Leucovorin is known to enhance efficacy of S-1, and we conducted this phase I trial of combination therapy of gemcitabine, S-1 and leucovorin (GSL).Methods
Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Gemcitabine was administered at an escalating dose of 600, 800 and 1,000 mg/m2 over 30 min on day 1, and oral S-1 at a dose of 40 mg/m2 twice daily and oral leucovorin at a dose of 25 mg twice daily on days 1–7, every 2 weeks. A standard “3 + 3” phase I dose escalation design was utilized.Results
Fifteen patients were enrolled across three dose levels. Three patients developed DLTs: two patients in level 1 (grade 3 anorexia in 1 and grade 3 anorexia, stomatitis and diarrhea in 1) and one patient in level 2 (grade 3 deep vein thrombosis). No DLT was observed in level 3. Response rate and the disease control rate were 33 and 93 %, respectively. The median PFS and OS were 5.4 and 16.6 months. Ten of 12 patients (83 %) with elevated CA19-9 at baseline had a ≥50 % decline.Conclusions
RD of gemcitabine in GSL was determined as 1,000 mg/m2. GSL was well tolerable and showed promising results in advanced pancreatic cancer. 相似文献19.
S. Agelaki E. Kontopodis A. Kotsakis V. Chandrinos I. Bompolaki Ζ. Zafeiriou E. Papadimitraki D. Stoltidis K. Kalbakis V. Georgoulias 《Cancer chemotherapy and pharmacology》2013,72(1):45-51
Purpose
To determine the dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of oral topotecan administered weekly in patients with relapsed small cell lung cancer (SCLC).Patients and methods
Patients were treated with oral topotecan on days 1, 8, and 15, every 28 days. The dose was escalated by 0.5 mg/m2 increments from the starting dose of 3 mg/m2 until the MTD was reached. DLTs were defined as grade 4 neutropenia, febrile neutropenia, grade 4 thrombocytopenia, non-hematologic toxicity ≥grade 3, any toxicity precluding the treatment on days 8 or 15 of the first cycle, or delay of the second cycle for more than 7 days.Results
Eighteen patients were enrolled. Thirteen patients received oral topotecan as second-line and five as third- or further-line treatment. The DLT level was reached at 4.5 mg/m2, and the MTD was determined to be 4 mg/m2. DLTs consisted of grade 2/3 neutropenia and grade 2 thrombocytopenia precluding treatment on day 15 of the first cycle or on day 1 of the second cycle. The most frequent toxicities were grade 2–3 neutropenia (27.8 % of patients), grade 2–3 anemia (33.3 %), grade 2 thrombocytopenia (16.7 %), and grade 2–3 fatigue (44.4 %). The response rate was 11.1 %, the median progression-free survival 2.3 months, and the median overall survival 5.1 months.Conclusion
The recommended phase II dose of weekly oral topotecan in pretreated patients with SCLC is 4 mg/m2 on days 1, 8, and 15 every 28 days. 相似文献20.
Sym SJ Hong J Jung M Park J Cho EK Lee WK Chung M Kim HS Lee JH Shin DB 《Cancer chemotherapy and pharmacology》2012,70(2):277-284